2-Decarboxy-2-tetrazolyl-PGI2 compounds

ABSTRACT

The present invention relates to 2-decarboxy-2-tetrazolyl-PGI 2  amides, having pharmacological activity. Particularly, the compounds described herein are useful as platelet aggregation inhibitors.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending application Ser. No. 819,940, filed July 28, 1977; and a continuation-in-part of Ser. No. 725,550, filed Sept. 22, 1976, now abandoned; and a continuation-in-part of Ser. No. 716,770, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel compositions of matter which are derivatives of prostacyclin or PGI₂. The chemical name for prostacyclin is (5Z)-5,6-didehydro-9-deoxy-6,9α-epoxy-PGF₁ α. Specifically the present invention relates to 2-decarboxy-2-tetrazolyl-PGI₂ compounds.

Prostacyclin itself was first reported as "PGX" by Moncada and his co-workers. See Moncada, et al., Prostaglandins 12:658-713 (1976). Prostacyclin is a circulating hormone in the arterial circulation of mammals. See "Prostacyclin As A Circulating Hormone", Nature 273:767-768 (June 29, 1978) and Grycleweski, R. J., et al., "Generation of Prostacyclin By Lungs In Vivo And Its Release Into Arterial Circulation", Nature 273:765-767 (June 29, 1978).

PRIOR ART

Subsequent to any invention described herein the existence of prostacyclin as a naturally-occurring composition of matter was reported in the aforementioned references.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR1## or a mixture comprising that compound and the enantiomer thereof wherein W₂ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, or α--CH₂ OH:β--H;

wherein L is

(1) --(CH₂)_(d) --C(R₂)₂ --,

(2) --CH₂ --O--CH₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈,

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₄ is

--C(R₅)(R₆)C_(g) H_(2g) --CH₃,

--C(R₅)(R₆)--Z--(Ph I), or

--CH₂ --CH═CH--CH₂ CH₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and (Ph I); wherein (Ph I) is phenyl optionally substituted by one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, with the proviso that not more than two such substituents are other than alkyl and such substituents being either the same or different; and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

Compounds in accordance with the present invention are prepared by chemical methods and have pharmacological uses as are described in U.S. Pat. No. 4,158,667, incorporated here by reference. Accordingly, compounds in accordance with the present invention are useful for a variety of pharmacological purposes. Accordingly, the compounds in accordance with the present invention are especially useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular drafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long-term prophylaxis following myocardial infarcts and strokes. For these purposes, the compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Dosages in the range about 0.01 to about 10 mg/kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The addition of these compounds to whole blood provides in vitro applications, such as storage of whole blood to be used in heart-lung machines. Additionally, whole blood containing these compounds can be circulated through limbs and organs, e.g., heart and kidneys, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. Blocking of aggregated platelets is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor person or animal, to the perfused whole body, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001-1.0 μg/ml of whole blood. These compounds are also useful in preparing platelet-rich concentrates from blood for use in treating thrombocytopenia or in chemotherapy. 

We claim:
 1. A compound of the formula ##STR2## or a mixture comprising that compound and the enantiomer thereof wherein W₂ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, or α--CH₂ OH:β--H;wherein L is(2) --(CH₂)_(d) --C(R₂)₂ --, (2) --CH₂ --O--CH₂ --Y--, or (3) --CH₂ CH═CH--, wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈, wherein R₈ is hydrogen or alkyl or one to 4 carbon atoms, inclusive, wherein R₄ is--C(R₅)(R₆)C_(g) H_(2g) --CH₃, --C(R₅)(R₆)--Z--(Ph I), or --CH₂ --CH═CH--CH₂ CH₃, wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and (Ph I); wherein (Ph I) is phenyl optionally substituted by one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, with the proviso that not more than two such substituents are other than alkyl and such substituents being either the same or different; and wherein X is(1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --; including the lower alkanoates thereof. 